Abstract
Despite the world’s combined efforts, human immunodeficiency virus (HIV), the causative agent of AIDS, remains one of the world’s most serious public health challenges. High genetic variability of HIV complicates the development of anti-HIV vaccine, and there is an actual clinical need for increasing the efficiency of anti-HIV drugs in terms of targeted delivery and controlled release. Tenofovir (TFV), a nucleotide-analog reverse transcriptase inhibitor, has gained wide acceptance as a drug for pre-exposure prophylaxis or treatment of HIV infection. In our study, we explored the potential of tenofovir disoproxil (TFD) adducts with block copolymers of poly(ethylene glycol) monomethyl ether and poly(ethylene phosphoric acid) (mPEG-b-PEPA) as candidates for developing a long-acting/controlled-release formulation of TFV. Two types of mPEG-b-PEPA with numbers of ethylene phosphoric acid (EPA) fragments of 13 and 49 were synthesized by catalytic ring-opening polymerization, and used for preparing four types of adducts with TFD. Antiviral activity of [mPEG-b-PEPA]TFD or tenofovir disoproxil fumarate (TDF) was evaluated using the model of experimental HIV infection in vitro (MT-4/HIV-1IIIB). Judging by the values of the selectivity index (SI), TFD exhibited an up to 14-fold higher anti-HIV activity in the form of mPEG-b-PEPA adducts, thus demonstrating significant promise for further development of long-acting/controlled-release injectable TFV formulations.
Highlights
Human immunodeficiency virus (HIV) is an infectious agent of acquired immunodeficiency syndrome (AIDS)
We explored the potential of tenofovir disoproxil (TFD) adducts with block copolymers of poly(ethylene glycol) monomethyl ether and poly(ethylene phosphoric acid) as candidates for developing a long-acting/controlled-release formulation of TFV
We synthesized two mPEG-b-PEPA copolymers differing in the PEPA chain length and prepared their adducts with TFD; the effect of such modifications on in vitro anti-human immunodeficiency virus (HIV) activity was further assessed in MT-4 cells infected with HIV-1IIIB
Summary
Human immunodeficiency virus (HIV) is an infectious agent of acquired immunodeficiency syndrome (AIDS). Combination antiretroviral therapy (cART; three drugs at a time, to be administered once daily) is a universally recognized means of the first-line treatment for HIV infection, making it possible to achieve suppression of viral replication and restoration of CD4 cell counts in the majority of patients. The majority of the investigated antiretroviral agents are not well suited for formulation as long-acting injectables due to suboptimal physicochemical properties limiting their formulation as conventional drug suspensions, as well as insufficient antiviral potency resulting in high monthly dosing requirements. An intriguing opportunity would lie within the development of long-acting, synthetic scaffolds for delivering antiretrovirals Those scaffolds should be designed with the goal to reduce the frequency of dosing and, hold the possibility of potential targeting of the drugs to key HIV residual sites [10]. Tfio-rHmIVulattheedrawpiyth seimncteric2it0a0b1i;neit) [h4a5s]. aInlstohibseceonmmapupnriocvateidonf,owr ePrreEpPort(atshamt noenwotlyheorbatpayineodr choy-dforormphuilaictebdlowckit-hcoepmoltyrimcietrasboinfem) e[4th5]y.laIntetdhpisoclyo(metmhyulneniceatgiloync,owl) e(mrePpEoGrt) tahnadt PnEewPAlygoivbetraisineeodf thhyedarnotpivhiirlaicl abcltoicvkit-ycoopfoTlFyVmeargsaionfstmHeItVhy-1laIItIBedinpMolTy-(4etcheylllse.ne glycol) (mPEG) and PEPA give rise of the antiviral activity of TFV against HIV-1IIIB in MT-4 cells
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